Process for the synthesis and crytalline form of agomelatine

ABSTRACT

A process for the industrial synthesis and new crystalline form of the compound of formula (I):  
                 
Medicinal products containing the same which are useful in treating disorders of the melatoninergic system.

FIELD OF THE INVENTION

The present invention relates to a process for the industrial synthesisof agomelatine, or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, offormula (I):

The present invention relates also to crystalline form II ofagomelatine, a process for its preparation and pharmaceuticalcompositions containing it.

BACKGROUND OF THE INVENTION

Agomelatine, or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, has valuablepharmacological properties.

Indeed it has the double feature of being, on the one hand, an agonistof melatoninergic system receptors and, on the other hand, an antagonistof the 5-HT_(2C) receptor. Those properties confer activity in thecentral nervous system and, more especially, in the treatment of severedepression, seasonal affective disorders, sleep disorders,cardiovascular pathologies, pathologies of the digestive system,insomnia and fatigue resulting from jetlag, appetite disorders andobesity.

DESCRIPTION OF THE PRIOR ART

Agomelatine, its preparation and its therapeutic use have been describedin European Patent Specification EP 0 447 285.

In view of the pharmaceutical value of this compound, it has beenimportant to be able to obtain it by an effective industrial synthesisprocess that is readily transposable to an industrial scale and thatresults in agomelatine in a good yield and with excellent purity.

It has been also important to be able to obtain agomelatine with welldefined crystalline form, perfectly reproducible, which as a resultexhibits valuable characteristics in terms of filtration and ease offormulation.

Patent Specification EP 0 447 285 describes the preparation ofagomelatine in eight steps, starting from 7-methoxy-1-tetralone, givingan average yield of less than 30%.

That process involves the action of ethyl bromoacetate, followed byaromatisation and saponification to yield the corresponding acid, whichis then converted to acetamide and subsequently dehydrated to yield(7-methoxy-1-naphthyl)acetonitrile, this being followed by reduction,and then condensation of the acetyl chloride.

In particular, the preparation of (7-methoxy-1-naphthyl)acetonitrileinvolves six reaction steps and, transposed to an industrial scale, hasquickly demonstrated the difficulties of carrying out the process, thesebeing caused principally by problems of reproducibility of the firststep, which constitutes the action of ethyl bromoacetate on7-methoxy-1-tetralone according to the Réformatsky reaction resulting inethyl (7-methoxy-3,4-dihydro-1(2H)-naphthalenylidene)ethanoate.

Moreover, the subsequent step of aromatisation of ethyl(7-methoxy-3,4-dihydro-1(2H)-naphthalenylidene)ethanoate has often beenincomplete and resulted, after saponification, in a mixture of productsthat is difficult to purify.

The literature describes obtaining (7-methoxy-1-naphthyl)acetonitrile inthree steps starting from 7-methoxy-1-tetralone, by the action ofLiCH₂CN followed by dehydrogenation with DDQ(2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and finally dehydration inacid medium (Synthetic Communication, 2001, 31(4), 621-629). The totalyield is mediocre (76%), however, and in particular the DDQ used in thedehydrogenation reaction and the benzene reflux necessary in the thirdstep do not comply with industrial requirements in terms of cost and theenvironment.

DETAILED DESCRIPTION OF THE INVENTION

The Applicant has now developed a new industrial synthesis process thatresults, in a reproducible manner and without the need for laboriouspurification, in agomelatine of a purity compatible with its use as apharmaceutical active ingredient.

An alternative to the difficulties encountered with the processdescribed in Patent Specification EP 0 447 285 has been obtained bydirectly condensing a cyano compound with 7-methoxy-1-tetralone. It wasin addition necessary that the condensation compound obtained couldreadily be subjected to aromatisation to yield(7-methoxy-1-naphthyl)acetonitrile without the need for drasticconditions, and that reagents compatible with industrial requirements interms of cost and the environment could be used.

It is apparent that (7-methoxy-3,4-dihydro-1-naphthalenyl)acetonitrilewould constitute an ideal synthesis intermediate that meets therequirements for direct synthesis from 7-methoxy-1-tetralone, and wouldbe an excellent substrate for the aromatisation step.

Reactions for the direct condensation of tetralones with acetonitrile oracetonitrile compounds are described in the literature. In particular,U.S. Pat. No. 3,992,403 describes the condensation of cyanomethylphosphonate with 6-fluoro-1-tetralone, and U.S. Pat. No. 3,931,188describes the condensation of acetonitrile with tetralone leading to acyano intermediate which is directly engaged in the subsequent reaction.Applied to 7-methoxy-1-tetralone, the condensation of acetonitrileyields a mixture of isomers in which “exo” constitutes the major portionand “endo” the minor portion, according to FIG. 1:

such a mixture requiring subsequent drastic aromatisation conditionsthat are not compatible with the industrial requirements for the purposeof carrying out the synthesis of agomelatine.

The Applicant has now developed a new industrial synthesis process thatallows (7-methoxy-1-naphthyl)acetonitrile to be obtained from7-methoxy-tetralone, in a reproducible manner and without the need forlaborious purification, in only two steps by using as synthesisintermediate (7-methoxy-3,4-dihydro-1-naphthalenyl)acetonitrile freefrom the “exo” impurity of formula (II):

which impurity cannot be subjected to subsequent aromatisation underoperating conditions that are compatible with the industrialrequirements for the purpose of carrying out the synthesis ofagomelatine.

More specifically, the present invention relates to a process for theindustrial synthesis of the compound of formula (I):

which is characterised in that 7-methoxy-1-tetralone of formula (III):

is reacted with cyanoacetic acid of formula (IV):

in conditions wherein the water formed is removed, in the presence of acatalytic amount of a compound of formula (V):

wherein R and R′, which may be the same or different, each represents alinear or branched (C₃-C₁₀)alkyl group, an unsubstituted or substitutedaryl group, or an unsubstituted or substituted linear or branched aryl(C₁-C₆)alkyl group,to yield, after filtration and washing with a basic solution,(7-methoxy-3,4-dihydro-1-naphthalenyl)acetonitrile of formula (VI):

which compound of formula (VI) is reacted with a hydrogenation catalystin the presence of an allyl compound to yield the compound of formula(VII):

which is then subjected to reduction with hydrogen in the presence ofRaney nickel in ammoniacal ethanol medium, and subsequently converted toa salt using hydrochloric acid to yield the compound of formula (VIII):

which is subjected successively to the action of sodium acetate and thenacetic anhydride to yield the compound of formula (I), which is isolatedin the form of a solidwherein:

-   -   aryl is understood to mean a phenyl, naphthyl or biphenyl group,    -   the term “substituted” governing the terms “aryl” and        “arylalkyl” denotes that the aromatic moiety of those groups may        be substituted by from 1 to 3 identical or different groups        selected from linear or branched (C₁-C₆)alkyl, hydroxy and        linear or branched (C₁-C₆)alkoxy,    -   “allyl compound” is understood as any molecule containing from 3        to 10 carbon atoms, which may contains in addition 1 to 5 oxygen        atoms, and containing at least one —CH₂—CH═CH₂ group.

More especially, in the reaction for the conversion of the compound offormula (III) to a compound of formula (VI), the water formed is removedby distillation. There is preferably used a reaction solvent that has aboiling temperature higher than or equal to that of water, and even morepreferably that forms an azeotrope with water, such as, for example,xylene, toluene, anisole, ethylbenzene, tetrachloroethylene, cyclohexeneor mesitylene.

Preferably, the conversion of the compound of formula (III) to thecompound of formula (VI) is carried out with reflux of toluene or xyleneand, more especially, with reflux of toluene.

In the reaction for the conversion of the compound of formula (III) to acompound of formula (VI), advantageously one of the groups R or R′ ofthe catalyst employed represents a linear or branched (C₃-C₁₀)alkylgroup and the other represents an aryl or arylalkyl group. Moreespecially, a preferred catalyst is that of formula (V_(a)):

wherein R′_(a) represents a phenyl group unsubstituted or substituted byone or more linear or branched (C₁-C₆)alkyl groups, n is 0 or 1, andR_(a) represents a linear (C₃-C₁₀)alkyl group.

Advantageously, R′_(a) represents an unsubstituted or substituted phenylgroup, more especially an unsubstituted phenyl group.

The preferred group R_(a) is the hexyl group.

The preferred value of n is 1.

The preferred catalyst used in the conversion of the compound of formula(III) to the compound of formula (VI) according to the process of theinvention is benzylammonium heptanoate of formula (IX):

Advantageously, the compound of formula (VI) is obtained afterfiltration and washing with a mineral or organic basic solution, such asNaOH, KOH, Ca(OH)₂, Sr(OH)₂ or NH₄OH, and more especially with a sodiumhydroxide solution.

Preferably, the conversion of the compound of formula (VI) to thecompound of formula (VII) is carried out with reflux of toluene orxylene, more especially with reflux of toluene.

The catalyst preferably used in the conversion of the compound offormula (VI) to the compound of formula (VII) is a catalyst either inoxide form or supported as for example palladium, platinum, nickel,Al₂O₃ and, more especially, palladium. Advantageously, 1 to 20%palladium-on-carbon will be used, and more particularly 5% or 10%palladium-on-carbon. Preferably, palladium-on-carbon will be used inamounts ranging from 1 to 10% by weight of catalyst in relation to theweight of substrate, and more especially 5%. The hydrogen acceptorpreferably used in the reaction for the conversion of the compound offormula (VI) to a compound of formula (VII) is an allyl compound and,more especially, an allyl acrylate or an allyl glycidyl ether. Thepreferred allyl acrylate of the process according to the invention isallyl methacrylate.

Advantageously, the conversion of the compound of formula (VII) to thecompound of formula (VIII) according to the process of the invention iscarried out at from 20 to 40° C., more especially at from 30 and 40° C.,and even more advantageously at 40° C.

Advantageously, the conversion of the compound of formula (VIII) to thecompound of formula (I) is carried out in alcoolic medium and moreparticularly in an ethanolic medium.

This process is of particular interest for the following reasons:

-   -   it allows the “endo” compound of formula (VI), exclusively, to        be obtained on an industrial scale. This result is altogether        surprising considering the literature relating to that type of        reaction, which most frequently reports obtaining “exo”/“endo”        mixtures (Tetrahedron, 1966, 22 3021-3026). The result is due to        the use of a compound of formula (V) as reaction catalyst        instead of the ammonium acetates currently used in such        reactions (Bull. Soc. Chim. Fr., 1949, 884-890).    -   the rate of conversion of the compound of formula (III) to the        compound of formula (VI) is very high, exceeding 97%, unlike        that which could be observed using acetic acid, for which the        rate does not exceed 75%.    -   the use of a hydrogenation catalyst in the presence of an allyl        compound for the conversion of the compound of formula (VI) to        the compound of formula (VII) is entirely compatible with        industrial requirements in terms of cost and the environment,        unlike the quinones currently used.    -   furthermore, it allows the compound of formula (VII),        exclusively, in particular free from the corresponding reduction        product of formula (X):        to be obtained on an industrial scale.    -   finally, the observed rates of conversion of the compound of        formula (VI) to the compound of formula (VII) are high,        exceeding 90%.    -   hydrogenation of the compound of formula (VII) in the presence        of Raney nickel in ammoniacal ethanol medium has been described        (J. Med. Chem., 1994, 37(20), 3231-3239), but requires        conditions that are difficult to apply to an industrial scale:        the reaction is carried out at 60° C. and for 15 hours, and the        final yield is less than 90%. Furthermore, a principal drawback        of that reaction is the concomitant formation of the “bis”        compound of formula (XI):        and the difficulty of controlling the conversion rate of that        impurity. The process developed by the Applicant allows the        compound of formula (VIII) to be obtained with a level of        impurity down to below 4% under experimental conditions that are        compatible with industrial requirements, since the reaction is        carried out at from 30 to 40° C. to give a yield exceeding 90%        and a chemical purity exceeding 99.5%.    -   the amidation step carried out in alcoolic medium and more        particularly in an ethanolic medium allows the compound of        formula (I) to be isolated very easily in a quantitative yield,        a result which is completely surprising since a reaction of that        type is not very compatible with that solvent, for which a        competitive consumption of acetic anhydride would be expected.

The compound of formula (VI) obtained according to the process of theinvention is new and is useful as an intermediate in the synthesis ofagomelatine, in which it is subjected to aromatisation followed byreduction and then to coupling with acetic anhydride.

The invention relates also to the crystalline II form of agomelatineobtained according to the process described above. It is, in fact,important to be able to obtain a well defined and perfectly reproduciblecrystalline form.

The prior art EP 0 447 285 and Yous et al. (Journal of MedicinalChemistry, 1992, 35 (8), 1484-1486) allows agomelatine to be obtained ina particular crystalline form which has been described in Tinant et al.(Acta Cryst., 1994, C50, 907-910).

The Applicant has now developed a process for obtaining agomelatine in awell-defined, perfectly reproducible, crystalline form and which as aresult exhibits valuable characteristics in terms of filtration and easeof formulation.

More specifically, the present invention relates to the crystalline IIform of agomelatine, characterised by the following parameters, obtainedfrom the powder diagram obtained using a Bruker AXS D8 high-resolutiondiffractometer having a 2θ angular range of 3°-90°, a step of 0.01° and30 s per step:

-   -   monoclinic crystal lattice    -   lattice parameters: a=20.0903 Å, b=9.3194 Å, c=15.4796 Å,        β=108.667°    -   space group : P2₁/n    -   number of molecules in the unit cell: 8    -   unit cell volume: V_(unit cell)=2746.742 Å³    -   density: d=1.13 g/cm³.

The crystalline form II of agomelatine of the present invention may alsobe characterised by the following powder X-ray diffraction data,measured using a diffractometer (copper anticathode) and expressed interms of inter-planar distance d (expressed in Å), Bragg's angle 2 theta(expressed in degrees), and relative intensity (expressed as apercentage with respect to the most intense ray): Angle 2 theta (°)Inter-planar distance d (Å) Intensity (%) 6.30 14.009 15 9.26 9.544 2310.50 8.419 13 12.65 6.995 50 13.29 6.655 13 15.34 5.771 24 15.81 5.59916 17.15 5.165 100 18.03 4.917 16 18.60 4.766 72 19.01 4.665 75 20.094.417 77 20.44 4.343 38 20.97 4.234 12 21.18 4.191 15

An advantage of obtaining that crystalline form is that it allowsespecially rapid and efficient filtration as well as the preparation ofpharmaceutical formulations having a consistent and reproduciblecomposition, which is especially advantageous when the formulations areto be used for oral administration.

The form so obtained is sufficiently stable to enable prolonged storagewithout special conditions in respect of temperature, light humidity oroxygen levels.

A pharmacological study of the form so obtained has demonstrated that ithas substantial activity in respect of the central nervous system and inrespect of microcirculation, enabling it to be established that thecrystalline II form of agomelatine is useful in the treatment of stress,sleep disorders, anxiety, severe depression, seasonal affectivedisorders, cardiovascular pathologies, pathologies of the digestivesystem, insomnia and fatigue due to jetlag, schizophrenia, panicattacks, melancholia, appetite disorders, obesity, insomnia, pain,psychotic disorders, epilepsy, diabetes, Parkinson's disease, seniledementia, various disorders associated with normal or pathologicalageing, migraine, memory loss, Alzheimer's disease, and in cerebralcirculation disorders. In another field of activity, it appears that thecrystalline II form of agomelatine can be used in the treatment ofsexual dysfunction, that it has ovulation-inhibiting andimmunomodulating properties and that it lends itself to use in thetreatment of cancers.

The crystalline II form of agomelatine will preferably be used in thetreatment of severe depression, seasonal affective disorders, sleepdisorders, cardiovascular pathologies, insomnia and fatigue due tojetlag, appetite disorders and obesity.

The invention relates also to pharmaceutical compositions comprising asactive ingredient the crystalline II form of agomelatine together withone or more appropriate inert, non-toxic excipients. Among thepharmaceutical compositions according to the invention there may bementioned, more especially, those which are suitable for oral,parenteral (intravenous or subcutaneous) or nasal administration,tablets or dragees, granules, sublingual tablets, gelatin capsules,lozenges, suppositories, creams, ointments, dermal gels, injectablepreparations, drinkable suspensions and disintegrable pastes.

The useful dosage can be adapted according to the nature and theseverity of the disorder, the administration route and the age andweight of the patient. The dosage varies from 0.1 mg to 1 g per day inone or more administrations.

The Examples below illustrate the invention but do not limit it in anyway.

EXAMPLE 1 N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide Step A:(7-Methoxy-3,4-dihydro-1-naphthalenyl)acetonitrile

There are introduced into a 670 litre reactor 85.0 kg of7-methoxy-1-tetralone, 60.3 kg of cyanoacetic acid and 15.6 kg ofheptanoic acid in toluene in the presence of 12.7 kg of benzylamine. Themixture is heated at reflux. When all the starting substrate hasdisappeared, the solution is cooled and filtered. The precipitateobtained is washed with toluene and then the filtrate obtained is washedwith a 2N sodium hydroxide solution and subsequently with water untilneutral. After removal of the solvent by evaporation, the resultingsolid is recrystallised from an ethanol/water (80/20) mixture to givethe title product in a yield of 90% and with a chemical purity exceeding99%.

Melting point: 48-50° C.

Step B: (7-Methoxy-1-naphthyl)acetonitrile

There are introduced into a 670 litre reactor 12.6 kg of 5%palladium-on-carbon in toluene, which is heated at reflux; then 96.1 kgof (7-methoxy-3,4-dihydro-1-naphthalenyl)-acetonitrile dissolved intoluene are added as well as 63.7 kg of allyl methacrylate. The reactionis continued at reflux and is followed by vapour phase chromatography.When all the starting substrate has disappeared, the reaction mixture iscooled to ambient temperature and then filtered. After removal of thetoluene by evaporation, the resulting solid residue is recrystallisedfrom an ethanol/water (80/20) mixture to give the title product in ayield of 91% and with a chemical purity exceeding 99%.

Melting point: 83° C.

Step C: 2-(7-Methoxy-1-naphthyl)ethanamine Hydrochloride

There are introduced into a 1100 litre reactor 80.0 kg of the compoundobtained in Step B, 24.0 kg of Raney nickel in ethanol and 170 l ofammonium hydroxide. The mixture is stirred under a hydrogen pressure of30 bars, then brought to 40° C. When all the starting substrate hasdisappeared, the solvent is evaporated off, the resulting residue isredissolved in ethyl acetate, and 41.5 l of an 11N hydrochloric acidsolution are added. After filtration, the precipitate obtained is washedwith ethyl acetate and then dried in an oven to give the title productin a yield of 95.3% and with a chemical purity exceeding 99.5%.

Melting point: 243° C.

Step D: N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide

173 kg of the compound obtained in Step C and 66 kg of sodium acetate inethanol are introduced into a 1600 litre reactor. The mixture is stirredand then 79 kg of acetic anhydride are added; the reaction mixture isheated at reflux and 600 l of water are added. The reaction mixture isallowed to return to ambient temperature and the precipitate obtained isfiltered off and washed with a 35/65 ethanol/water mixture to give thetitle product in a yield of 92.5% and with a chemical purity exceeding99%.

Melting point: 108° C.

EXAMPLE 2 N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide Step A:(7-Methoxy-3,4-dihydro-1-naphthalenyl)acetonitrile

There are introduced into a 670 litre reactor 85.0 kg of7-methoxy-1-tetralone, 60.3 kg of cyanoacetic acid and 15.6 kg ofheptanoic acid in toluene in the presence of 11.0 kg of aniline. Themixture is heated at reflux. When all the starting substrate hasdisappeared, the solution is cooled and filtered. The precipitateobtained is washed with toluene and then the filtrate obtained is washedwith a 2N sodium hydroxide solution and subsequently with water untilneutral. After removal of the solvent by evaporation, the resultingsolid is recrystallised from an ethanol/water (80/20) mixture to givethe title product in a yield of 87% and with a chemical purity exceeding99%.

Melting point: 48-50° C.

Step B: (7-Methoxy-1-naphthyl)acetonitrile

The procedure is as in Step B of Example 1.

Melting point: 83° C.

Step C: 2-(7-Methoxy-1-naphthyl)ethanamine Hydrochloride

The procedure is as in Step C of Example 1.

Melting point. 243° C.

Step D: N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide

The procedure is as in Step D of Example 1.

Melting point: 108° C.

EXAMPLE 3 Crystalline II form ofN-[2-(7-methoxy-1-napthyl)ethyl]acetamide

Data recording was carried out using a Bruker AXS D8 high-resolutiondiffractometer with the following parameters: a 2θ angular range of3°-90°, a step of 0.01° and 30 s per step. TheN-[2-(7-methoxy-1-napthyl)ethyl]acetamide powder obtained in Example 1was deposited on a transmission mounting support. The X-ray source is acopper tube (λCuK_(α1)=1.54056 Å). The mounting comprises a frontmonochromator (Ge(111) crystal) and an energy-resolved solid-statedetector (MXP-D1, Moxtec-SEPH).

The compound is well crystallised: the ray width at half-height is ofthe order of 0.07° (2θ). The following parameters were thus determined:

-   -   monoclinic crystal lattice    -   lattice parameters: a=20.0903 Å, b=9.3194 Å, c=15.4796 Å,        β=108.667°    -   space group : P2₁/n    -   number of molecules in the unit cell: 8    -   unit cell volume: V_(unit cell)=2746.742 Å³    -   density: d=1.13 g/cm₃

EXAMPLE 4 Pharmaceutical Composition

Formulation for the preparation of 1000 tablets each containing a doseof 25 mg: Compound of Example 3 25 g Lactose monohydrate 62 g Magnesiumstearate 1.3 g Maize starch 26 g Maltodextrines 9 g Silica, colloidalanhydrous 0.3 g Sodium starch glycolate type A 4 g Stearic acid 2.6 g

EXAMPLE 5 Pharmaceutical Composition

Formulation for the preparation of 1000 tablets each containing a doseof 25 mg: Compound of Example 3 25 g Lactose monohydrate 62 g Magnesiumstearate 1.3 g Povidone 9 g Silica, colloidal anhydrous 0.3 g Sodiumcellulose glycolate 30 g Stearic acid 2.6 g

1. A crystalline form II of agomelatine of formula (I):

having a powder X-ray diffraction diagram exhibiting peaks at 6.30,9.26, 10.50, 12.65, 13.29, 15.34, 15.81, 17.15, 18.03, 18.60, 19.01,20.09, 20.44, 20.97, and 21.18 deg 2 theta.
 2. A pharmaceuticalcomposition comprising as active ingredient, an effective amount of thecompound of claim 1, in combination with one or more pharmaceuticallyacceptable, inert, non-toxic carriers.
 3. A method for treating a livinganimal body, including a human, afflicted with disorders of themelatoninergic system, comprising the step of administering to theliving animal body, including a human, an amount of the compound ofclaim 1 which is effective for treatment of the disorder.
 4. The methodof claim 3, wherein the disorder of the melatoninergic system isselected from sleep disorders, stress, anxiety, seasonal affectivedisorders or severe depression, cardiovascular pathologies, pathologiesof the digestive system, insomnia and fatigue due to jetlag,schizophrenia, panic attacks, melancholia, appetite disorders, obesity,insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease,senile dementia, various disorders associated with normal orpathological ageing, migraine, memory loss, Alzheimer's disease,cerebral circulation disorders, and also in sexual dysfunction, asovulation inhibitors, immunomodulators and cancers.